1. Field of the Invention
This invention relates to treatments for acute lung injury (ALI).
2. Description of the Related Art
ALI is a common clinical syndrome characterized by lung alveolar injury, disruption of the alveolar capillary barrier, a neutrophilic inflammatory response, and marked pulmonary physical dysfunction as assessed by oxygenation, lung compliance, and airway resistance. ALI is caused by a wide variety of insults including trauma, infection, sepsis, and inhalation or aspiration of toxic substances or chemicals.
In patients who develop ALI, the most common and sever manifestation is respiratory failure. Insults leading to ALI cause disruption of the alveolar capillary barrier and alveolar injury. This results in leakage of fluid into the alveoli and marked thickening and inflammation of the alveolar walls. This, in turn, interferes with the ability of the alveoli to deliver inhaled oxygen to the blood. As a result, ALI patients display sever hypoxemia, which can be observed as low blood oxygen levels, which are often incompatible with normal tissue function.
The current state of the art treatment for ALI is supportive care. ALI patients are typically placed on ventilator support in an ICU setting. In recent years, the only significant advances in the treatment of ALI relate to the specifics of how this ventilator support is provided. There presently exists no pharmacologic agents that reduce the major physiologic cause of ALI, namely, disruption of the alveolar capillary barrier, or that reduce the severity or mortality of ALI.
Inducible (or type 2) nitric oxide synthase (iNOS) is known to be related to inflammation conditions. For example, Dugo et al. “Effects of GW274150, a novel and selective inhibitor of iNOS activity, in acute lung inflammation”, British Journal of Pharmacology, 141, pp. 979-987 (2004) reports that iNOS inhibitors can be effective in treating various inflammatory diseases. However, no evidence has been presented nor has it been hypothesized that this relation to inflammatory conditions would have any implications for the treatment of ALI.
iNOS is also known to be related to the development of bleomycin-induced lung injury. For example, Genovese et al. “Inhibition or knock out of Inducible nitric oxide synthase result in resistance to bleomycin-induced lung injury” Respiratory Research, 6:58 (2005) reports that iNOS plays a role in development of bleomycin-inducted lung injury. However, bleomycin-induced lung injury is a separate and distinct condition from ALI and no evidence has been presented nor has it been hypothesized that knowledge regarding the development and treatment of bleomycin-induced lung injury is related to or predictive of development and treatment of ALI.
Accordingly, a need exists for methods and compositions for the treatment of ALI, particularly for treatment of ALI resulting from inhalation of aspiration of toxic substances, such as chlorine.